Effect of chronic kidney disease induced calcification on peripheral vascular perfusion using near-infrared spectroscopic imaging.

Low-cost techniques that can detect the presence of vascular calcification (VC) in chronic kidney disease (CKD) patients could improve clinical outcomes. In this study, we established a near-infrared spectroscopy-based imaging technique to determine changes in peripheral hemodynamics due to CKD-induced VC. Mice were fed a high-adenine diet with either normal or high levels of phosphate to induce CKD with and without VC, respectively. The mice tail was imaged to evaluate hemodynamic changes in response to occlusion. The rate of change in oxyhemoglobin in response to occlusion showed a statistically significant difference in the presence of VC in the mice.

Diabetic Foot Ulcer Imaging: An Overview and Future Directions.

Diabetic foot ulcers (DFUs) affect one in every three people with diabetes. Imaging plays a vital role in objectively complementing the gold-standard visual yet subjective clinical assessments of DFUs during the wound treatment process. Herein, an overview of the various imaging techniques used to image DFUs is summarized. Conventional imaging modalities (e.g., computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emitted computed tomography, and ultrasound) are used to diagnose infections, impact on the bones, foot deformities, and blood flow in patients with DFUs. Transcutaneous oximetry is a gold standard to assess perfusion in DFU cases with vascular issues. For a wound to heal, an adequate oxygen supply is needed to facilitate reparative processes. Several optical imaging modalities can assess tissue oxygenation changes in and around the wounds apart from perfusion measurements. These include hyperspectral imaging, multispectral imaging, diffuse reflectance spectroscopy, near-infrared (NIR) spectroscopy, laser Doppler flowmetry or imaging, and spatial frequency domain imaging. While perfusion measurements are dynamically monitored at point locations, tissue oxygenation measurements are static two-dimensional spatial maps. Recently, we developed a spatio-temporal NIR-based tissue oxygenation imaging approach to map for the extent of asynchrony in the oxygenation flow patterns in and around DFUs. Researchers also measure other parameters such as thermal maps, bacterial infections (from fluorescence maps), pH, collagen, and trans-epidermal water loss to assess DFUs. A future direction for DFU imaging would ideally be a low-cost, portable, multi-modal imaging platform that can provide a visual and physiological assessment of wounds for comprehensive wound care intervention and management.

Spatial-Temporal Oxygenation Mapping Using a Near-Infrared Optical Scanner: Towards Peripheral Vascular Imaging.

Near-infrared spectroscopy (NIRS)-based peripheral perfusion, or microcirculation, can be used to assess the severity of peripheral vascular dysfunction. A low-cost, portable non-contact near-infrared optical scanner (NIROS) was developed for spatio-temporal mapping of tissue oxygenation and perfusion in tissues. In vivo validation studies were carried out on control subjects (n = 3) to assess the ability of NIROS to measure real-time oxygenation changes in response to an occlusion paradigm on the dorsum of the hand. NIROS captured real-time tissue oxygenation changes with 95% correlation when compared to a commercial device. A feasibility peripheral imaging study was performed in a mouse model (n = 5) of chronic kidney disease (CKD) induced vascular calcification to assess differences in microcirculatory peripheral tissue oxygenation. The tissue oxygenation (in terms of oxy-, deoxy-, and total hemoglobin changes) due to the occlusion paradigm was distinctly different prior to (week-6) and after the onset of vascular calcification (week-12) in the murine tails. Future work will involve extensive studies to correlate these microcirculatory tissue oxygenation changes in the peripheral tail to the vascular calcification in the heart.

Assessment of Tissue Oxygenation and Radiation Dermatitis Pre-, During, and Post-Radiation Therapy in Breast Cancer Patients.

Over 95% of breast cancer patients treated with radiation therapy (RT) undergo an adverse skin reaction known as radiation dermatitis (RD). Assessment of severity or grading of RD is clinically visual and hence subjective. Our objective is to determine sub-clinical tissue oxygenation (oxygen saturation) changes in response to RT in breast cancer patients using near-infrared spectroscopic imaging and correlate these changes to RD grading. A 4-8 week longitudinal pilot imaging study was carried out on 10 RT-treated breast cancer patients. Non-contact near-infrared spectroscopic (NIRS) imaging was performed on the irradiated ipsilateral and the contralateral breast/chest wall, axilla and lower neck regions before RT, across the weeks of RT, and during follow-up after RT ended. Significant changes (p < 0.05) in oxygen saturation (StO2) of irradiated and contralateral breast/chest wall and axilla regions were observed across weeks of RT. The overall drop in StO2 was negatively correlated to RD scaling (in 7 out of 9 cases) and was higher in the irradiated regions when compared to its contralateral region. Differences in the pre-RT StO2 between ipsilateral and contralateral chest wall is a potential predictor of the severity of RD. The subclinical recovery of StO2 to its original state was longer than the visual recovery in RD grading scale, as observed from the post-RT assessment of tissue oxygenation.

Tissue Oxygenation Measurements to Aid Scalpel Debridement Removal in Patients With Diabetes.

BACKGROUND: Callus formation in the diabetic foot increases the risk of ulcer onset. It is standard procedure to remove these dead tissue layers to reduce rising pressures. In a surgical procedure known as scalpel debridement, or chiropody the callus tissue is removed up to the epidermal layer. Factors may influence the outcome of this surgical process such as clinician inexperience. In an effort to standardize the debridement process, tissue oxygenation (TO) measurements are obtained before and after to study the effect of debridement on callus tissue. METHODS: Fifteen debridement cases were analyzed using near infrared (NIR) imaging to study changes in TO. The NIR-based device used in this study estimates effective changes in TO in terms of oxy-, deoxy-, total hemoglobin, and oxygen saturation. Weber contrasts between callus tissue and the surrounding normal tissue were compared following debridement for all TO parameters. In a secondary analysis, callus tissue was segmented into quadrants and a percent of significance (in terms of total TO change) was calculated using a t-test. RESULTS: Results show majority of cases displayed greater than 80% as the significant change in TO following debridement, except in cases with the presence of blood clot (a common precursor for ulceration). In cases where incomplete debridement was suspected, a significant change in TO was still observed. CONCLUSIONS: With extensive systematic studies in the future, NIR imaging technique to measure changes in TO may be implemented as a low-cost hand-held imaging device useful for objectively assessing the effectiveness of the scalpel debridement process.

Development of a Smartphone-Based Optical Device to Measure Hemoglobin Concentration Changes for Remote Monitoring of Wounds.

Telemedicine (TM) can revolutionize the impact of diabetic wound care management, along with tools for remote patient monitoring (RPM). There are no low-cost mobile RPM devices for TM technology to provide comprehensive (visual and physiological) clinical assessments. Here, a novel low-cost smartphone-based optical imaging device has been developed to provide physiological measurements of tissues in terms of hemoglobin concentration maps. The device (SmartPhone Oxygenation Tool-SPOT) constitutes an add-on optical module, a smartphone, and a custom app to automate data acquisition while syncing a multi-wavelength near-infrared light-emitting diode (LED) light source (690, 810, 830 nm). The optimal imaging conditions of the SPOT device were determined from signal-to-noise maps. A standard vascular occlusion test was performed in three control subjects to observe changes in hemoglobin concentration maps between rest, occlusion, and release time points on the dorsal of the hand. Hemoglobin concentration maps were compared with and without applying an image de-noising algorithm, single value decomposition. Statistical analysis demonstrated that the hemoglobin concentrations changed significantly across the three-time stamps. Ongoing efforts are in imaging diabetic foot ulcers using the SPOT device to assess its potential as a smart health device for physiological monitoring of wounds remotely.

Breath-Hold Paradigm to Assess Variations in Oxygen Flow in Diabetic Foot Ulcers Using a Noncontact Near-Infrared Optical Scanner.

Objective: Diabetic foot ulcers (DFUs) occur in almost 25% of all patients with diabetes in their lifetime, with oxygen being the key limiting factor in healing. Identifying regions of compromised oxygenated flow can help clinicians cater the wound treatment process, possibly reducing wound healing time. Herein, a handheld, noncontact near-infrared optical scanner (NIROS) was developed and used to measure temporal changes in hemoglobin concentrations in response to a breath-hold (BH) paradigm. Approach: Noncontact imaging studies were carried out on DFU subjects and control subjects in response to a 20-s BH paradigm. Continuous-wave-based multiwavelength diffused reflective signals were acquired to generate effective oxy-hemoglobin, deoxy-hemoglobin, total hemoglobin, and oxygen saturation concentration maps using modified Beer-Lambert's law. Pearson's correlation analysis was carried out to determine variations in oxygen flow from hemoglobin concentration maps and the extent of variation observed in controls versus DFU subjects. Results: Temporal changes in hemoglobin concentration maps were observed in controls and DFU subjects. However, the oxygen flow in response to BH varied within 10% in all controls but significantly varied between wound and background regions in subjects with DFUs. Innovation: A method to assess variations in oxygen supply in and around DFUs was demonstrated using NIROS. This approach has potential to better cater DFU treatment process. Conclusion: Changes in all hemoglobin parameters due to 20 s of BH was observed. Pearson's analysis indicates that oxy-hemoglobin, deoxy-hemoglobin, and oxygen saturation fluctuations are synchronous in controls. In DFUs, changes are asynchronous with blood flow between the wound region and background region being significantly different.

Tissue Oxygenation Changes to Assess Healing in Venous Leg Ulcers Using Near-Infrared Optical Imaging.

Objective: Venous leg ulcers (VLUs) comprise 80% of leg ulcers. One of the key parameters that can promote healing of VLUs is tissue oxygenation. To date, clinicians have employed visual inspection of the wound site to determine the healing progression of a wound. Clinicians measure the wound size and check for epithelialization. Imaging for tissue oxygenation changes surrounding the wounds can objectively complement the subjective visual inspection approach. Herein, a handheld noncontact near-infrared optical scanner (NIROS) was developed to measure tissue oxygenation of VLUs during weeks of treatment. Approach: Continuous-wave-based diffuse reflectance measurements were processed using Modified Beer-Lambert's law to obtain changes in tissue oxygenation (in terms of oxy-, deoxy-, total hemoglobin, and oxygen saturation). The tissue oxygenation contrast obtained between the wound and surrounding tissue was longitudinally mapped across weeks of treatment of four VLUs (healing and nonhealing cases). Results: It was observed that wound to background tissue oxygenation contrasts in healing wounds diminished and/or stabilized, whereas in the nonhealing wounds it did not. In addition, in a very slow-healing wound, wound to background tissue oxygenation contrasts fluctuated and did not converge. Innovation: Near-infrared imaging of wounds to assess healing or nonhealing of VLUs from tissue oxygenation changes using a noncontact, handheld, and low-cost imager has been demonstrated for the first time. Conclusion: The tissue oxygenation changes in wound with respect to the surrounding tissue can provide an objective subclinical physiological assessment of VLUs during their treatment, along with the gold-standard visual clinical assessment.

Development and Validation of a Smartphone-Based Near-Infrared Optical Imaging Device to Measure Physiological Changes In-Vivo.

Smartphone-based technologies for medical imaging purposes are limited, especially when it involves the measurement of physiological information of the tissues. Herein, a smartphone-based near-infrared (NIR) imaging device was developed to measure physiological changes in tissues across a wide area and without contact. A custom attachment containing multiple multi-wavelength LED light sources (690, 800, and 840 nm; and <4 mW of optical power per LED), source driver, and optical filters and lenses was clipped onto a smartphone that served as the detector during data acquisition. The ability of the device to measure physiological changes was validated via occlusion studies on control subjects. Noise removal techniques using singular value decomposition algorithms effectively removed surface noise and distinctly differentiated the physiological changes in response to occlusion. In the long term, the developed smartphone-based NIR imaging device with capabilities to capture physiological changes will be a great low-cost alternative for clinicians and eventually for patients with chronic ulcers and bed sores, and/or in pre-screening for potential ulcers in diabetic subjects.

Assessing the Healing of Venous Leg Ulcers Using a Noncontact Near-Infrared Optical Imaging Approach.

Objective: Venous leg ulcers (VLUs) are one of the most common complications in lower extremity wounds. To date, clinicians employ visual inspection of the wound site during its healing process by monitoring surface granulation and reduction in wound size across weeks of treatment. In this study, a handheld near-infrared optical scanner (NIROS) has been developed at the Optical Imaging Laboratory to differentiate healing from nonhealing VLUs based on differences in blood flow to the wound and its surroundings. Approach: Noncontact near-infrared (NIR) area imaging of 12 VLUs have been carried out at two podiatric clinics. Diffuse reflectance images of the wounds were used to quantify optical contrasts between the wound and its surroundings. The variability in imaging conditions, analysis, and operator dependency were assessed to determine the robustness of the imaging approach. Results: Optical contrast obtained from diffuse reflectance images of VLUs were distinctly different for healing (positive contrast) and nonhealing (negative contrast) wounds, independent of the varying imaging and data analysis conditions. Innovation: NIR imaging of wounds to differentiate healing from nonhealing VLUs using a noncontact wide-area imager has been demonstrated for the first time. Conclusion: The application of a portable handheld imager to assess the healing or nonhealing nature of VLUs during weekly clinical treatment is significant since physiological changes, as observed using NIROS, manifest before visual reduction in wound size during the healing process.

Near-Infrared Fluorescence-Enhanced Optical Tomography.

Fluorescence-enhanced optical imaging using near-infrared (NIR) light developed for in vivo molecular targeting and reporting of cancer provides promising opportunities for diagnostic imaging. The current state of the art of NIR fluorescence-enhanced optical tomography is reviewed in the context of the principle of fluorescence, the different measurement schemes employed, and the mathematical tools established to tomographically reconstruct the fluorescence optical properties in various tissue domains. Finally, we discuss the recent advances in forward modeling and distributed memory parallel computation to provide robust, accurate, and fast fluorescence-enhanced optical tomography.

Critical Review of Noninvasive Optical Technologies for Wound Imaging.

Significance: Noninvasive imaging approaches can provide greater information about a wound than visual inspection during the wound healing and treatment process. This review article focuses on various optical imaging techniques developed to image different wound types (more specifically ulcers). Recent Advances: The noninvasive optical imaging approaches in this review include hyperspectral imaging, multispectral imaging, near-infrared spectroscopy (NIRS), diffuse reflectance spectroscopy, optical coherence tomography, laser Doppler imaging, laser speckle imaging, spatial frequency domain imaging, and fluorescence imaging. The various wounds imaged using these techniques include open wounds, chronic wounds, diabetic foot ulcers, decubitus ulcers, venous leg ulcers, and burns. Preliminary work in the development and implementation of a near-infrared optical scanner for wound imaging as a noncontact hand-held device is briefly described. The technology is based on NIRS and has demonstrated its potential to differentiate a healing from nonhealing wound region. Critical Issues: While most of the optical imaging techniques can penetrate few hundred microns to a 1-2 mm from the wound surface, NIRS has the potential to penetrate deeper, demonstrating the potential to image internal wounds. Future Directions: All the technologies are currently at various stages of translational efforts to the clinic, with NIRS holding a greater promise for physiological assessment of the wounds internal, beyond the gold-standard visual assessment.

Optical imaging for breast cancer prescreening.

Breast cancer prescreening is carried out prior to the gold standard screening using X-ray mammography and/or ultrasound. Prescreening is typically carried out using clinical breast examination (CBE) or self-breast examinations (SBEs). Since CBE and SBE have high false-positive rates, there is a need for a low-cost, noninvasive, non-radiative, and portable imaging modality that can be used as a prescreening tool to complement CBE/SBE. This review focuses on the various hand-held optical imaging devices that have been developed and applied toward early-stage breast cancer detection or as a prescreening tool via phantom, in vivo, and breast cancer imaging studies. Apart from the various optical devices developed by different research groups, a wide-field fiber-free near-infrared optical scanner has been developed for transillumination-based breast imaging in our Optical Imaging Laboratory. Preliminary in vivo studies on normal breast tissues, with absorption-contrasted targets placed in the intramammary fold, detected targets as deep as 8.8 cm. Future work involves in vivo imaging studies on breast cancer subjects and comparison with the gold standard X-ray mammography approach.

Noninvasive Surface Imaging of Breast Cancer in Humans using a Hand-held Optical Imager.

X-ray mammography, the current gold standard for breast cancer detection, has a 20% false-negative rate (cancer is undetected) and increases in younger women with denser breast tissue. Diffuse optical imaging (DOI) is a safe (nonionizing), and relatively inexpensive method for noninvasive imaging of breast cancer in human subjects (including dense breast tissues) by providing physiological information (e.g. oxy- and deoxy- hemoglobin concentration). At the Optical Imaging Laboratory, a hand-held optical imager has been developed which employs a breast contourable probe head to perform simultaneous illumination and detection of large surfaces towards near real-time imaging of human breast cancer. Gen-1 and gen-2 versions of the handheld optical imager have been developed and previously demonstrated imaging in tissue phantoms and healthy human subjects. Herein, the hand-held optical imagers are applied towards in vivo imaging of breast cancer subjects in an attempt to determine the ability of the imager to detect breast tumors. Five female human subjects (ages 51-74) diagnosed with breast cancer were imaged with the gen-1 optical imager prior to surgical intervention. One of the subjects was also imaged with the gen-2 optical imager. Both imagers use 785 nm laser diode sources and ICCD camera detectors to generate 2D surfaces maps of total hemoglobin absorption. The subjects lay in supine position and images were collected at various locations on both the ipsilateral (tumor-containing) and contralateral (non-tumor containing) breasts. The optical images (2D surface maps of optical absorption due to total hemoglobin concentration) show regions of higher intensity at the tumor location, which is indicative of increased vasculature and higher blood content due to the presence of the tumor. Additionally, a preliminary result indicates the potential to image lymphatic spread. This study demonstrates the potential of the hand-held optical devices to noninvasively image breast cancer in human subjects.

Motor response investigation in individuals with cerebral palsy using near infrared spectroscopy: pilot study.

Cerebral palsy (CP) describes a group of motor impairment syndromes secondary to genetic that may be due to acquired disorders of the developing brain. In this study, near infrared spectroscopy (NIRS) is used to investigate the prefrontal cortical activation and lateralization in response to the planning and execution of motor skills in controls and individuals with CP. The prefrontal cortex, which plays a dominant role in the planning and execution of motor skill stimulus, is noninvasively imaged using a continuous wave-based NIRS system. During the study, 7 controls (4 right-handed and 3 left-handed) and 2 individuals with CP (1 right-handed and 1 left-handed) over 18 years of age performed 30 s of a ball throwing task followed by 30 s rest in a 5-block paradigm. The optical signal acquired from the NIRS system was processed to elucidate the activation and lateralization in the prefrontal region of controls and individuals with CP. The preliminary result indicated a difference in activation between the task and rest conditions in all the participant types. Bilateral dominance was observed in the prefrontal cortex of controls in response to planning and execution of motor skill tasks, while an ipsilateral dominance was observed in individuals with CP. In conjunction, similar contralateral dominance was observed during rest periods, both in controls and individuals with CP.

Functional connectivity in the brain in joint attention skills using near infrared spectroscopy and imaging.

In this study, the changes in activation in terms of Oxy-Hemoglobin (HbO) and Deoxy-Hemoglobin (HbR) were detected in response to join attention based tasks in normal adults using near infrared spectroscopy and imaging. With these detections, functional connectivity between the left and right sides of frontal region of the brain was measured and modeled by a lagged covariance structural equation modeling (SEM). Statistical analysis was performed to assess the difference in the path coefficients amongst different stimuli (joint attention, non-joint attention, and baseline rest). The results demonstrate that the left and right sides of the frontal region of the brain interacted with each other distinctly in response to the joint and non-joint attention based stimuli.

Three-dimensional fluorescence tomography of human breast tissues in vivo using a hand-held optical imager.

Diffuse optical imaging using non-ionizing radiation is a non-invasive method that shows promise towards breast cancer diagnosis. Hand-held optical imagers show potential for clinical translation of the technology, yet they have not been used towards 3D tomography. Herein, 3D tomography of human breast tissue in vivo is demonstrated for the first time using a hand-held optical imager with automated coregistration facilities. Simulation studies are performed on breast geometries to demonstrate the feasibility of 3D tomographic imaging using a hand-held imager under perfect (1:0) and imperfect (100:1, 50:1) fluorescence absorption contrast ratios. Experimental studies are performed in vivo using a 1 µM ICG filled phantom target placed non-invasively underneath the flap of the breast tissue. Results show the ability to perform automated tracking and coregistered imaging of human breast tissue (with tracking accuracy on the order of ∼1 cm). Three-dimensional tomography results demonstrated the ability to recover a single target placed at a depth of 2.5 cm, from both the simulated (at 1:0, 100:1 and 50:1 contrasts) and experimental cases on actual breast tissues. Ongoing efforts to improve target depth recovery are carried out via implementation of transmittance imaging in the hand-held imager.

Resolution of a Gen-2 handheld optical imager: diffuse and fluorescence imaging studies.

A generation-2 (Gen-2) handheld optical imager capable of two-dimensional surface and three-dimensional tomographic imaging has recently been developed. Herein, the ability of the handheld imager to detect and resolve two targets under diffuse and fluorescence imaging conditions has been demonstrated via tissue phantom studies. Two-dimensional surface imaging studies demonstrated that two 0.96 cm diameter Indocyannine Green targets were detected and resolved ~0.5 cm apart (between edges) at a target depth of 1 cm during diffuse imaging and up to 2 cm depth during fluorescence imaging. Preliminary 3D tomographic imaging capability to resolve the two targets was also demonstrated, but requires extensive future studies.

Hand-held optical imager (Gen-2): improved instrumentation and target detectability.

Hand-held optical imagers are developed by various researchers towards reflectance-based spectroscopic imaging of breast cancer. Recently, a Gen-1 handheld optical imager was developed with capabilities to perform two-dimensional (2-D) spectroscopic as well as three-dimensional (3-D) tomographic imaging studies. However, the imager was bulky with poor surface contact (~30%) along curved tissues, and limited sensitivity to detect targets consistently. Herein, a Gen-2 hand-held optical imager that overcame the above limitations of the Gen-1 imager has been developed and the instrumentation described. The Gen-2 hand-held imager is less bulky, portable, and has improved surface contact (~86%) on curved tissues. Additionally, the forked probe head design is capable of simultaneous bilateral reflectance imaging of both breast tissues, and also transillumination imaging of a single breast tissue. Experimental studies were performed on tissue phantoms to demonstrate the improved sensitivity in detecting targets using the Gen-2 imager. The improved instrumentation of the Gen-2 imager allowed detection of targets independent of their location with respect to the illumination points, unlike in Gen-1 imager. The developed imager has potential for future clinical breast imaging with enhanced sensitivity, via both reflectance and transillumination imaging.